If a small molecule is shown to be readily absorbed from the GI tract in pre-clinical studies (rat and dog) - what does this really indicate? How can this information assist in the clinical development of a product?
Whether physico-chemical properties fit, the drug shall presents a pKa value suitable for diffusion and penetration on cells in experimental model tested; this hypothesis must be explored in clinical human tests and does not guarantee the exactly the same result.
Thank you both for your prompt response. Does it indicate bio-availability?
"readily absorbed" is a general term usually used in the discussion of a paper, after stating the bioavailability. I assume a "readily absorbed" oral molecule would be greater than 50% of the dose-normalized AUC following iv administration, where Bioavailability (F) is F = [AUC(po) x Dose (iv)] / [AUC (iv) x Dose (po)] x 100. AUC (po) is usually (almost always) determined via systemic blood sampling, rather than portal vein sampling due to the difficultly of the latter. Thus, AUC (po) is determined after first-pass metabolism by the liver.
Hi. (Systemic) absorption and bioavailability are often used interchangeably. However, there may be a difference between absorption and bioavailability. This can occur in particular in the case of liver first pass: the compound is absorbed from the gut into the portal vein but is metabolized extensively by the liver before it reaches the site of sample collection (usually a venous return). In other words good absorption is required for good oral bioavailability but good absorption does not always guarantee good bioavailability.
You may realize this for example by dosing radioactive compound and observe that radioactivity is well absorbed, despite poor bioavailability assessed by a specific bioanalytical assay. Let's say you saw this in the rat.
This could be of relevance for clinical development. You may for example expect absorption in human to be as good as in your rat experiment (other data is indicative of passive absorption). If humans are expected to have slower hepatic metabolism than the rat (e.g. quantitative assessment based on in vitro rat and human liver microsome or hepatocyte data), then liver first pass could be expected to be low in human and both absorption and bioavailability may be high in human. Best.
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